Clopidogrel Hydrogen Sulfate (CAS: 135046-48-9) is the sulfate of clopidogrel. Its English name is Clopidogrel Hydrogen Sulfate and chemical name is (s)-α-(2-Chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H) acetate hydrogen sulfate. As an anti-platelet aggregation agent, Clopidogrel Hydrogen Sulfate is developed by Sanofi-aventis in France and marketed firstly in Britain and America in 1998. Clopidogrel Hydrogen Sulfate was marketed in China in 2001, and is clinically used for the prevention of atherosclerosis and thrombosis. At present, Clopidogrel Hydrogen Sulfate preparations in China mainly are Plavix manufactured by Sanofi-aventis and Talcom manufactured by Shenzhen Salubris Pharmaceutical Co., Ltd.

Clopidogrel Hydrogen Sulfate mainly exist as types I and II crystal form, of which type II is thermodynamic stable crystal and dissolution of corresponding preparation is slightly poor; While type I is thermodynamic unstable crystal form.
Currently, the marketed Clopidogrel Hydrogen Sulfate preparations mostly use type I crystal form, but Clopidogrel Hydrogen Sulfate crystal type I crystal form is not stable in damp and/or hot environment. Therefore, the conventional wet granulation-compressing process is not applicable to Clopidogrel Hydrogen Sulfate preparation, and dry method process is commonly used currently. The Clopidogrel Hydrogen Sulfate powder shows strong static electricity and stickiness, which make it easy to sticking in dry method process, thus to cause unsuccessful production. Although lubricant can avoid sticking, it is reported that conventional alkaline lubricants, such as magnesium stearate, have great effect on the stability of active ingredient, and sticking also occurs while using other conventional lubricants due to low melting point.
One of the feasible programs to solve the issue above is to make active ingredient exist as powder/crystal with good mobility and no electrostatic phenomenon. And current technologies mostly use mixed solvent to prepare spherical Clopidogrel Hydrogen Sulfate crystal form I.
Chinese patent CN201180072203.6 discloses a method for the preparation of spherical Clopidogrel Hydrogen Sulfate crystal form I, using 2-butanol/cyclohexane system to prepare spherical crystallization with size distributions d(0.1)=52.536 μm, d(0.5)=74.567 μm and d(0.9)=106.074 μm. The crystallization improves the mobility of Clopidogrel Hydrogen Sulfate, and reduces electrostatic phenomenon greatly. However, solvent used in this process is 2-butanol-cyclohexane mixture, of which cyclohexane is the solvent of category II enumerated in relevant regulations, such as Guideline for the Study on Residual Solvent of Chemical Drugs, and belongs to solvents required to be restricted for use during drug preparation, and there is strict requirement on its residual; at the same time, mixed solvent brings inconvenience in the recovery and utilization of the solvent. In addition, one of the critical technical factors of this process is that sulfuric acid and cyclohexane solution shall be added slowly into solvent system under cooling condition, which makes this process complex, and cyclohexane may change color due to the addition of concentrated sulfuric acid, thus affects quality of product; moreover, this process needs longer time, which, on one hand, has risk of crystal form transformation, on the other hand reduces the bulk density of product. Patent WO2011083955 discloses a method for the preparation of Clopidogrel Hydrogen Sulfate spherical crystallization, of which the solvent used to prepare spherical crystallization in example 5 is 2-butanol-water mixture. But water, used in solvent of this process, has a high boiling point, it needs longer time and higher temperature to be removed in the follow-up process; In addition, water also goes against the generation crystal form. Yield of this process is just 53% which is in a lower level. In the comparison example 1 of this patent, it studies the effect of usage amount of water on product modality, and the result shows that single 2-butanol solvent system is not in favor of the formation of spherical crystallization and Clopidogrel Hydrogen Sulfate obtained is disorganized powder as shown in patent FIG. 4. Therefore, to search a Clopidogrel Hydrogen Sulfate spherical crystallization I of environmentally friendly, low cost, high yield and whose character meets the requirements of the follow-up preparation process, is still a technical issue not solved with available technologies.